ABSTRACT The long-term product goal of this project is a small molecule therapeutic for choroidal neovascularization (CNV, the hallmark of wet age-related macular degradation), an abnormal growth of blood vessels in the choroid layer of the eye that results in damage to the retina and consequent blindness. Our lead compound is the natural product sterculic acid, which has been shown to inhibit CNV in animal models. The main current treatment options for CNV involves intravitreal injection of anti-VEGF agents such as ranibizumab (Lucentis), aflibercept (Eylea) and (in off-label use) bevacizumab (Avastin) which, while often slowing disease progression, have a number of side-effects associated with the method of administration. A small molecule therapeutic which might be administered topically would present obvious advantages. Sterculic acid has very recently been shown to mitigate the induction of CNV in a rat model and to antagonize the inflammatory effects of 7- ketocholesterol (7KCh) in cultured human retinal pigment epithelium cells. However the molecule has a number of potential liabilities from the perspective of a pharmaceutically useful agent, including difficulty of isolation from natural sources, instability and lack of selectivity, which need to be addressed in parallel with a desire to also increase potency. We therefore propose to prepare analogs of sterculic acid and evaluate them in assays predictive of CNV activity and off-target selectivity. The goal of this current Phase I SBIR project is to identify analogs of sterculic acid with greater potency and improved pharmacokinetics in a range of predictive in vitro assays with minimal off-target effects. These tasks will be accomplished by carrying out a broad structure-activity relationship (SAR) study on sterculic acid - preparing a series of analogs that probe the relative importance of the existing structural features of the lead compound with a consequent optimization of activity (Aim 1) and, in parallel, preparing a further analog series which probes the pharmacokinetic space around the lead compound, utilizing analogs with water-solubilizing functionality, stabilizing groups, and acid bioisosteres resulting in improved stability, optimal logD and greater solubility (Aim 2). We will analyze the efficacy of these compounds utilizing established in vitro assays for inhibition of 7KCh-induced retinal pigmented epithelium cell inflammatory and apoptotic responses, inhibition of stearoyl CoA desaturase, and favorable pharmacokinetic properties. A successful project is expected to yield several novel inhibitors of 7KCh-induced inflammatory responses suitable for Phase II refined SAR and pharmacokinetic studies and evaluation in a rat model of CNV. We anticipate that these compounds will be potent inhibitors of CNV that can serve as leads for the development of small molecule AMD drugs with greater efficacy and preferable delivery compared to existing treatments.